Conventional means for delivering active agents are often severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, or the target itself.
Biologically or chemically active agents are particularly vulnerable to such barriers. For example in the delivery to humans and animals of pharmacological and therapeutic agents, barriers are imposed by the body. Examples of physical barriers are the skin and various organ membranes that must be traversed before reaching a target. Chemical barriers include, but are not limited to, pH variations, lipid bilayers, and degrading enzymes. These barriers are of particular significance in the design of oral delivery systems. Oral delivery of many biologically or chemically active agents would be the route of choice for administration to humans and animals if not for biological, chemical, and physical barriers such as varying pH in the gastro-intestinal (GI) tract, powerful digestive enzymes, and active agent impermeable gastro-intestinal membranes. Among the numerous agents which are not typically amenable to oral administration are biologically or chemically polar organic compounds, such as cromolyn, antibiotics and other organic substances. These agents are rapidly rendered partially or totally ineffective, pass through partially or totally unabsorbed, or are partially or totally destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes, or the like.
Earlier methods for orally administering vulnerable pharmacological agents, such as polar organic compounds and biological macromolecules have relied on the co-administration of adjuvants (e.g., resorcinols and non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to artificially increase the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and aprotinin) to inhibit enzymatic degradation.
The oral administration of therapeutic agents that require parenteral administration would greatly improve patient compliance and reduce the costs and risks associated with injections. Absorption of drugs via the gastrointestinal (GI) tract, however, is hampered by natural barriers including acid-induced hydrolysis in the stomach, enzymatic degradation throughout the GI tract, poor solubility in the intestinal environment, and lack of permeation through the epithelial cells. The latter is particularly problematic because it can exclude the passage of compounds across the tissue based on size, charge and/or lipophilicity. A common strategy to overcome this obstacle is the use of general penetration enhancers and/or nonspecific protease inhibitors. These systems, however, are highly inefficient and have been shown to cause transient to long-lasting membrane damage. Such membrane effects have the added disadvantage of allowing nonselective transport of toxic materials.
In current practice, cromolyn sodium is used by inhalation as a prophylactic agent in the treatment of mild to moderate asthma, as a nasal inhaler to treat seasonal bronchial asthma and as an ophthalmic solution to treat allergic or vernal conjunctivitis. Cromolyn is a mast cell stabilizer and as such attacks the initial step in the cascade that results in the manifestation of allergy including asthma and allergic rhinitis. The mechanism of action of cromolyn is through inhibiting the release of histamine and leukotrienes from the mast cells. Cromolyn has a high safety profile but exhibits poor absorption from the gastrointestinal tract. The clinical practicality and patient compliance of this drug is reduced because it is available mainly as an inhalation agent, and several weeks of therapy may be required before improvement is apparent. Cromolyn, when given orally, is poorly absorbed from the gastrointestinal tract because it is highly lipid-insoluble and mainly ionized.
Cromolyn is available only as an inhalation agent, except for an oral concentrate commercially available in the United States under the trade name Gastrocrom® from Celltech Pharmaceuticals, Inc. Gastrocrom® is provided in 5 ml ampoules containing 100 mg cromolyn sodium, USP, in purified water. Gastrocrom® is indicated in the management of patients with mastocytosis, and use of this product is said to be associated with improvement in diarrhea, flushing, headaches, vomiting, uticaria, abdominal pain, nausea and itching in some patients. No more than 1% of an administered dose of Gastrocrom® is absorbed by humans after oral administration (Physician's Desk Reference® 2001, page 1840-1841).
Many investigators believe that if cromolyn were to be available in an oral form and with good absorption from the gastrointestinal tract, it would become a valuable addition with broad application in the treatment of allergic asthma and rhinitis.